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Enantioselective Synthesis of OasomycinA Part III Fragment Assembly and Confirmation of Structure.

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DOI: 10.1002/ange.200603652
Natural Products Synthesis
Enantioselective Synthesis of Oasomycin A, Part III: Fragment
Assembly and Confirmation of Structure**
David A. Evans,* Pavel Nagorny, Kenneth J. McRae, Louis-Sebastian Sonntag,
Dominic J. Reynolds, and Filisaty Vounatsos
Dedicated to Professor Y. Kishi on the occasion of his 70th birthday.
Herein we address the total synthesis of the natural product
oasomycin A by assembly of the C1–C12, C13–C28, and
C29–C46 subunits, whose syntheses have been described in
the preceding Communications.[1]
The synthesis plan (Scheme 1) incorporates a speculative
late-stage macrolactonization of the linear seco acid precursor to form a 42-membered lactone that upon global
deprotection would provide the natural product. Since
oasomycin A is known to rearrange to the oasomycins D
and E under basic conditions,[2] an acid-mediated global
deprotection was obligatory. It was our intention to assemble
the requisite seco acid by using an aldol addition of the
C1–C28 ketone I to the C29–C46 aldehyde II with a
concomitant installation of the C29 stereocenter, followed
by a stereoselective reduction of the C27 ketone.
The assembly of ketone I through a Kocienski–Julia
olefination[3] of the C13–C28 aldehyde III with C1–C12
fragment IV was undertaken first (Scheme 2). Sulfone 1 was
selectively deprotonated with KHMDS and treated with
aldehyde 2[3] to afford the coupling product 3 a as a 7:1
mixture of E/Z isomers (57 % yield). In addition, a significant
amount of a by-product was consistently formed in 15–25 %
Scheme 1. Assembly of oasomycin A subunits.
[*] Prof. D. A. Evans, P. Nagorny, Dr. K. J. McRae, Dr. L.-S. Sonntag,
Dr. D. J. Reynolds, Dr. F. Vounatsos
Department of Chemistry & Chemical Biology
Harvard University
Cambridge, MA 02138 (USA)
Fax: (+ 1) 617–495–1460
[**] Financial support has been provided by the National Institutes of
Health (GM-33327-19), the Merck Research Laboratories, Amgen,
and Eli Lilly. A postdoctoral fellowship was provided to L.-S.S. by the
Deutscher Akademischer Austauschdienst and the Novartis Foundation, and to D.J.R. by the Glaxo Foundation.
Supporting information for this article is available on the WWW
under or from the author.
Angew. Chem. 2007, 119, 551 –554
yield in this and related olefinations. This by-product with the
general structure 3 b (Scheme 2) may be rationalized by a
Brook rearrangement of the Julia intermediate followed by
alkoxide attack on the sulfur center. All efforts to suppress
this side reaction were unsuccessful.[4]
With both the C1–C28 and C29–C46 subunits in hand, we
addressed the aldol coupling which would provide the
oasomycin A skeleton. The logic behind the selection of an
aldol addition to form the C28C29 bond was based on the
fact that the diastereoselectivity of this reaction should be
reinforced by resident chirality in both reaction partners: the
C25 stereocenter on the enolate [Eq. (1)],[5] and the C31
stereocenter on the aldehyde fragment [Eq. (2)].[6] Although
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 2. Construction of the C1–C28 subunit 3 a. Reagents and
conditions: a) 1. 1, KHMDS, DME, 46 8C; 2. 2, DME, 46 8C!RT,
(57 %, 7:1 E/Z). DME = 1,2-dimethoxyethane, HMDS = hexamethyldisilazide, PMB = 4-methoxybenzyl, TBS = tert-butyldimethylsilyl,
TES = triethylsilyl.
the selected aldol addition should proceed through the antiFelkin pathway, the chosen control elements should be
dominant in determining the reaction diastereoselectivity.[7]
Indeed, during our preliminary studies,[8] the Bu2BOTfmediated aldol addition of ketone 4 to aldehydes 5 a and
5 b, proceeded in good yield and diastereoselectivity to afford
the desired alcohol stereochemistry at C29 (Scheme 3).[9]
From prior studies, it was known that benzylic protecting
groups at C31 and C25 were required for good diastereoselectivity. The comparative reactions illustrated in Equations 1
and 2 reinforce this important point.
The assembly of oasomycin A began with the Wacker
oxidation of terminal olefin 3 a to methyl ketone 8
(Scheme 4). Since 3 a has low solubility in polar solvents, a
stoichiometric amount of PdCl2 in aqueous THF buffered
with Cu(OAc)2 was used for this oxidation.[10] The resulting
methyl ketone 8 was transformed into its derived boron
enolate and added to the C29–C46 aldehyde 9 to afford the
oasomycin A seco acid derivative 10 (78 %, > 10:1 d.r.).[11]
Chelate-controlled reduction of 10 (Zn(BH4)2, CH2Cl2/Et2O,
25 8C) provided the corresponding boronic acid diester
Scheme 3. Model studies for the aldol addition. Reagents and conditions: a) 1. 4, Bu2BOTf, iPr2NEt, Et2O, 78 8C; 2. 5, Et2O, 78 8C.
PMP = 4-methoxyphenyl, Tf = trifluoromethanesulfonyl.
(>10:1 d.r.), which was hydrolyzed (PPTS, CH2Cl2/MeOH)
with concurrent deprotection of the C43 TMS ether followed
by protection of the formed diol to afford acetonide 11 (75 %,
3 steps).[12] The hydrolysis of 11 mediated by LiOH effected
cleavage of both the C1 methyl ester and C46 lactone
moieties, and the resultant diacid was relactonized in acidified
chloroform to afford the seco acid 12.
Macrolactonization of 12 posed a problem as the standard
Yamaguchi procedure[13] provided only minor amounts of
macrolactone 13 a accompanied by its D3-olefin isomer 13 b
along with the symmetric anhydride 13 c as the predominant
product. In addition, investigation of the various lactonization
conditions reported by the research groups of Yonemitsu,
Shiina, and Keck[14] did not result in any improvement in the
yield of 13 a. After considerable effort, modified lactonization
conditions were developed to deliver the desired lactone 13 a
in 58 % yield. It was found that an excess of 2,4,6-trichlorobenzoyl chloride (17 equiv) and HCnig base (43 equiv)
followed by addition of the mixed anhydride to DMAP
(91 equiv) in toluene (25 8C) over two hours was required to
suppress the isomerization of the mixed anhydride to 13 c and
minimize the deconjugation to 13 b.[15]
Having prepared lactone 13 a, the deprotection of the
resident protecting groups was addressed. Oxidative removal
of the PMB groups (DDQ, CH2Cl2, pH 7 buffer, 0 8C) was
followed by treatment of the derived diol with hydrofluoric
acid (CH2Cl2, CH3CN, H2O, 7 8C, 4 d) to afford synthetic
oasomycin A (60 %, 2 steps).[16] At this point we do not have
clear evidence of the D3 oasomycin A that would result from
the by-product 13 b. The spectroscopic data of the synthetic
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2007, 119, 551 –554
Scheme 4. Final assembly. Reagents and conditions: a) PdCl2, Cu(OAc)2, THF/H2O, 75 %; b) 1. 8, Bu2BOTf, iPr2NEt, Et2O, 78 8C; 2. 9, Et2O,
78 8C, 78 %; c) Zn(BH4)2, CH2Cl2/Et2O, 25 8C; d) PPTS, CH2Cl2/MeOH (1:1), 0 8C; e) PPTS, 2,2-dimethoxypropane, (75 %, 3 steps); f) LiOH,
THF/MeOH/H2O; g) TFA (0.5 mol. %), CHCl3, (80 %, 2 steps); h) 1. 2,4,6-trichlorobenzoyl chloride (17 equiv), iPr2NEt (43 equiv), THF; 2. DMAP
(91 equiv), toluene, 2 h addition, 25 8C, 58 %; i) DDQ, CH2Cl2/pH 7 buffer, 0 8C; j) 1. HF, CH2Cl2/CH3CN/H2O, 0!7 8C; 2. TMSOMe, 7!20 8C,
(60 %, 2 steps). DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMAP = 4-dimethylaminopyridine, PPTS = pyridinium p-toluenesulfonate,
TFA = trifluoroacetic acid, TMS = trimethylsilyl.
material were consistent with those for the natural oasomycin A,[17] as evident from the 1H and 13C NMR spectra,
HPLC-MS/UV traces, and optical rotation ([a]D = 8.8,
c = 1.5 versus the reported [a]D = 13.1, c = 0.122).[18]
Herein and in the preceding Communications,[1] we have
reported the asymmetric synthesis of oasomycin A based on
the structural assignment made by Kishi and co-workers.[19]
On the basis of the spectroscopic data of the synthetic and
natural samples, we conclude that the stereochemical assignment for oasomycin A is correct. As a final note in passing,
the 42-membered macrolactonization reported in this synthesis is among the largest carboxy-activated ring closure yet
reported in the literature.[20] An unrelated macrocyclization
that has extended the precedent for achieving such ring
closures may be found in the synthesis of swinholide A
(44-membered lactone) reported by Paterson et al.[21] HowAngew. Chem. 2007, 119, 551 –554
ever, one should be cautious of concluding that such chemical
events are now routine.
Received: September 6, 2006
Published online: December 8, 2006
Keywords: aldol reaction · Kocienski–Julia olefination ·
macrolactonization · natural products · total synthesis
[1] a) D. A. Evans, P. Nagorny, K. J. McRae, D. J. Reynolds, L.-S.
Sonntag, F. Vounatsos, R. Xu, Angew. Chem. 2007, 119, 543 –
546; Angew. Chem. Int. Ed. 2007, 46, 537 – 540; b) D. A. Evans, P.
Nagorny, D. J. Reynolds, K. J. McRae, Angew. Chem. 2007, 119,
547 – 550; Angew. Chem. Int. Ed. 2007, 46, 541 – 544.
[2] M. Mayer, R. Thiericke, J. Chem. Soc. Perkin Trans. 1 1993,
2525 – 2531.
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
[3] P. J. Kocienski, A. Bell, P. R. Blakemore, Synlett 2000, 365 – 366.
For a recent review on this topic, see: P. R. Blakemore, J. Chem.
Soc. Perkin Trans. 1 2002, 2563 – 2585.
[4] Our attempts to further optimize the Kocienski–Julia olefination
were unsuccessful. In our model studies, the use of LiHMDS
eliminates the side product, but decreases the E/Z ratio of the
D12-olefin isomers to 2:1. Protection of the C15 alcohol as a
triisopropylsilyl ether significantly diminishes the reactivity of
the aldehyde because of steric hindrance.
[5] a) I. Paterson, K. R. Gibson, R. M. Oballa, Tetrahedron Lett.
1996, 37, 8585 – 8588; b) D. A. Evans, P. J. Coleman, B. CMtN, J.
Org. Chem. 1997, 62, 788 – 789.
[6] a) D. A. Evans, M. J. Dart, J. L. Duffy, J. Am. Chem. Soc. 1996,
118, 4322 – 4343; b) D. A. Evans, J. L. Duffy, M. J. Dart, Tetrahedron Lett. 1994, 35, 8537 – 8540.
[7] a) D. A. Evans, B. CMtN, P. J. Coleman, B. T. Connell, J. Am.
Chem. Soc. 2003, 125, 10 893 – 10 898; b) L. C. Dias, A. M.
Aguilar, A. G. Salles, L. J. Steil, W. R. Roush, J. Org. Chem.
2005, 70, 10 461 – 10 465.
[8] D. A. Evans, P. Nagorny, unpublished results. Also see Ref. [7a]
for precedent for this coupling.
[9] The stereochemistry of the C29 stereocenter was proven by the
Mosher ester analysis. See: J. A. Dale, H. S. Mosher, J. Am.
Chem. Soc. 1973, 95, 512 – 519.
[10] E. Kim, D. M. Gordon, W. Schmid, G. M. Whitesides, J. Org.
Chem. 1993, 58, 5500 – 5507.
[11] The inseparable impurity (ca. 9 %) that arose from the Wacker
oxidation of 3 a and that was present in the ketone 8 starting
material obscured the precise determination of the reaction
diastereoselectivity with the lower limit of detection set at 10:1.
[12] The stereochemistry of the reduction was proven by analysis of
the 13C NMR shift of the acetonide moiety. See:a) S. D. Rychnovsky, D. J. Skalitzky, Tetrahedron Lett. 1990, 31, 945 – 948;
b) S. D. Rychnovsky, B. Rogers, G. Yang, Tetrahedron Lett. 1990,
31, 3511 – 3515; c) D. A. Evans, D. L. Rieger, J. R. Gage,
Tetrahedron Lett. 1990, 31, 7099 – 7100.
[13] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 – 1993.
[14] a) M. Hikota, H. Tone, K. Horita, O. Yonemitsu, J. Org. Chem.
1990, 55, 7 – 9; b) I. Shiina, M. Kubota, R. Ibuka, Tetrahedron
Lett. 2002, 43, 7535 – 7539; c) E. P. Boden, G. E. Keck, J. Org.
Chem. 1985, 50, 2394 – 2395.
[15] For further details, see the Supporting Information.
[16] We found the optimal concentration of HF for the deprotection
was 1–2 m, at 7 8C as more concentrated solutions of HF or higher
temperatures decompose oasomycin A. Minor amounts of
mono-TBS-protected oasomycin A (ca. 10–20 %) were also
recovered after workup and then recycled. The yield reported
was calculated after one such recycling.
[17] We thank Professor Y. Kishi for providing the natural samples of
oasomycin A and B.
[18] S. Grabley, G. Kretzschmar, M. Mayer, S. Philipps, R. Thiericke,
J. Wink, A. Zeeck, Liebigs Ann. Chem. 1993, 5, 573 – 579.
[19] Y. Kobayashi, S.-H. Tan, Y. Kishi, J. Am. Chem. Soc. 2001, 123,
2076 – 2078, and references therein.
[20] A. Parenty, X. Moreau, J. -M. Campagne, Chem. Rev. 2006, 106,
911 – 939.
[21] I. Paterson, K.-S. Yeung, R. A. Ward, J. D. Smith, J. G. Cumming, S. Lamholey, Tetrahedron 1995, 51, 9467 – 9486.
2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2007, 119, 551 –554
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structure, synthesis, part, assembly, confirmation, enantioselectivity, fragmenty, iii, oasomycina
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